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FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF23 signaling and regulating FGF23 expression in bone

Woehrle, Simon and Bonny, Olivier and Beluch, Noemie and Gaulis, Swann and Stamm, Christelle and Scheibler, Marcel and Mueller, Matthias and Kinzel, Bernd and Thuery, Anne and Brueggen, Josef and Hynes, Nancy and Sellers, William and Hofmann, Francesco and Graus Porta, Diana (2011) FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF23 signaling and regulating FGF23 expression in bone. Journal of Bone and Mineral Research. ISSN 0884-0431

Abstract

The functional interaction between Fibroblast growth factor 23 (FGF23) and Klotho in the control of vitamin D and phosphate homeostasis is manifested by the largely overlapping phenotypes of Fgf23- and Klotho-deficient mouse models. However, to date targeted inactivation of FGF receptors (FGFRs) has not provided clear evidence for an analogous function of FGFRs in this process. Here, by means of pharmacological inhibition of FGFRs we demonstrate their involvement in renal FGF23/Klotho signaling and prove their role in the control of phosphate and vitamin D homeostasis. Specifically, FGFR loss of function counteracts renal FGF23/Klotho signaling leading to the deregulation of Cyp27b1 and Cyp24a1 and the induction of hypervitaminosis D and hyperphosphatemia. In turn, this initiates a feedback response leading to high serum levels of FGF23. Further, we show that FGFR inhibition blocks Fgf23 transcription in bone, and that this is dominant over vitamin D-induced Fgf23 expression, ultimately impinging on systemic FGF23 protein levels. Additionally, we identify Fgf23 as a specific target gene of FGF signaling in vitro. Thus, in line with Fgf23- and Klotho-deficient mouse models, our study illustrates the essential function of FGFRs in the regulation of vitamin D and phosphate levels. Further, we reveal FGFR signaling as a novel control mechanism for Fgf23 expression in bone, suggesting a dual function of FGFRs in the FGF23/Klotho pathway leading to vitamin D and phosphate homeostasis.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); On personal web site or secure external website at authors institution; Publisher's version/PDF cannot be used
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4197

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